Post-traumatic stress disorder (PTSD) is characterized by a variety of symptoms ranging from emotional despair to cognitive impairments related to trauma exposure. This project proposes a novel theory that the development of PTSD stems from impairments of brain inhibitory networks regulating emotion, cognition, and motor control. Neurobiological measurement techniques used to examine these inhibitory circuits may result in various intermediate constructs, referred to as endophenetypes, which may provide valuable insight about the mechanisms underlying PTSD development. Our preliminary data indicate a GABA-mediated, dopamine/serotonin- sensitive, short interval cortical inhibition (SICI) and intra-cortical facilitation (ICF) measured through transcranial magnetic stimulation (TMS) is associated with combat related PTSD. The objective of this application is to integrate clinical assessments, neurophysiological measurements, and molecular genetics to investigate the relationship of cortical inhibitory control and the mental health of veterans exposed to combat stress, specifically focusing on combat-related PTSD symptoms in Operation Iraq Freedom / Operation Enduring Freedom (OIF/OEF) Veterans. We propose three specific aims: 1) To identify cortical inhibition and excitability deficit (endophenotype) in PTSD. 2) To Determine monoamine transporter genes influencing SICI/ICF; 3) To explore GABA/glutamate system genetic variants in relation to SICI/ICF and PTSD. In the proposed study, we plan to recruit OIF/OEF combat Veterans with and without PTSD, and civilan healthy control without trauma exposure. Subject phenotype and symptom severity will be fully assessed using PTSD diagnostic and rating scales. Single and pair-pulse TMS over the motor cortex will be performed to assess SICI and ICF. Polymorphisms in monoamine transporter genes and GABA/glutamate system genes will be examined. Fine mapping techniques will be utilized via tagging single nucleotide polymorphisms (SNP) to cover the common variation of genetic loci of interest. Association among diagnostic category, symptom severity, SICI/ICF amplitude, and genotypes will be analyzed. Pairwise linkage disequilibrium (LD) will be estimated. The quantitative trait loci (QTL) approach will be applied to determine genetic markers that are strongly associated with the PTSD endophenotype. Several statistical models will be applied to analyze gene effects on endophenotype and PTSD phenotype. We expect that impaired SICI/ICF are related to PTSD, and that functional monoamine transporter genotypes and GABA/glutamatergic system gene polymorphisms are associated with both impaired SICI/ICF and PTSD symptomatology. The proposed work is innovative, because the hypothesis is novel and it integrates both molecular genetics and neurophysiologic endophenotype approaches in attempting to elucidate the mechanisms of PTSD development. The outcomes of the proposed study will have a significant impact in future genetic, diagnostic, and treatment research.